Integrated insights into gut microbiota and metabolomic landscape in breast cancer patients undergoing adjuvant endocrine therapy

Abstract

Gut microbiota and systemic metabolites are critical for breast cancer progression and therapeutic response. This study investigated gut microbiota and metabolic profiles of breast cancer patients before and after adjuvant endocrine therapy (AET). Using 16S rRNA sequencing and untargeted metabolomics, we identified significant disruptions in microbial diversity and metabolic pathways. Alpha diversity was reduced in pre-AET patients, with partial restoration observed post-AET. Key genera, such as Bifidobacterium and Coprococcus, were enriched in pre-AET patients, whereas Proteus and Methylobacterium were enriched in post-AET patients. Metabolomic analysis revealed significant reductions in the levels of vitamin B6 metabolites in both the pre-AET and post-AET groups compared to those in the healthy control (HC) group, indicating potential nutrient deficiencies or metabolic stress. Elevated cholesterol and estrogen metabolite levels in pre-AET patients reflect dysregulated lipid and hormone metabolism, with post-AET decreases in estrogen metabolites, confirming therapeutic efficacy. Correlation analysis revealed that Klebsiella_724518 was positively correlated with estrogen and vitamin B6 metabolites, whereas Proteus, Methylobacterium, Treponema_D, and Holdemanella were negatively correlated with cholesterol. Receiver operating characteristic (ROC) curve analysis identified estriol (area under the curve [AUC] = 1.000) as a strong diagnostic biomarker for distinguishing HCs from pre-AET patients, whereas cholesterol (AUC = 0.880) and estradiol-17β (AUC = 0.870) were highly effective in monitoring the therapeutic response to AET. This study highlights the role of gut microbiota and its metabolic byproducts in breast cancer development and treatment outcomes. It also reveals promising microbial and metabolite signatures for non-invasive cancer detection, tracking progression, and monitoring treatment response.IMPORTANCEBreast cancer progression and treatment response remain challenging to predict and monitor effectively. Our findings demonstrate the dual role of the gut microbiota and its metabolic products in influencing both. Strong correlations between specific microbial taxa and key metabolites provide new mechanistic insights into the influence of gut microbes on therapeutic outcomes during endocrine therapy. Importantly, we identified high-performance biomarkers, with estriol showing perfect diagnostic accuracy (AUC = 1.000) and cholesterol effectively monitoring treatment response (AUC = 0.880), highlighting their potential for non-invasive clinical applications. This study provides a foundation for applying gut microbiome research to develop clinical tools that could improve breast cancer management.

Keywords: adjuvant endocrine therapy; breast cancer; gut microbiota; metabolomics; microbial biomarkers; steroid hormone biosynthesis; vitamin B6 metabolism.